While the normal immune system is closely regulated, aberrations in immune responses are not uncommon. In some instances, the immune system functions inappropriately and reacts to a component of the host as if it were, in fact, foreign. Such a response results in an autoimmune disease, in which the host's immune system attacks the host's own tissue. T cells, as the primary regulators of the immune system, directly or indirectly affect such autoimmune pathologies.
T cell-mediated inflammatory diseases refer to any condition in which an inappropriate T cell response is a component of the disease. This includes both diseases directly mediated by T cells, and also diseases in which an inappropriate T cell response contributes to the production of abnormal antibodies.
Numerous diseases are believed to result from autoimmune mechanisms. Prominent among these are rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Type I diabetes, myasthenia gravis, pemphigus vulgaris. Autoimmune diseases affect millions of individuals world-wide and the cost of these diseases, in terms of actual treatment expenditures and lost productivity, is measured in billions of dollars annually.
The existence of peripheral autoimmune T cells that recognize dominant self-antigens is a property of all healthy immune systems. The immunological dominance of self antigens such as myelin basic protein (MBP), HSP60 and insulin is associated with cellular networks consisting of the self-reacting T cells together with a network of regulatory T cells that recognize and respond to the autoimmune T cells. The two main regulatory T cells are anti-idiotypic T cells and anti-ergotypic T cells (ergon in Greek=work, action).
While anti-idiotypic T cells appear to recognize the self-antigen receptors present on the pathogenic endogenous autoimmune T cells, the anti-ergotypic T cells are defined as T cells that respond to activated, syngeneic T cells independent of their idiotypic specificities. Anti-ergotypic T cells recognize as antigens the markers of the state of activation, ergotopes, of activated T cells. An example of such ergotope is the a chain of the IL-2 receptor (CD25), whose expression is up-regulated in activated T cells during T cell activation (Minami et al 1993; Taniguchi and Minami 1993). Anti-ergotypic T cells do not appear to respond to their target T cells in the resting state.
A comparison between the anti-ergotypic regulatory T cells and the anti-idiotypic regulatory T cells, although having some features in common, also reveals a difference in cytokine profile. While anti-idiotypic regulatory T cells secrete Th1 cytokines (Cohen 2001; Kumar et al 2001), the anti-ergotypic regulatory T cells secrete mainly IL-10, a Th2 cytokine.
Experimental autoimmune encephalomyelitis (EAE) is a T cell mediated autoimmune disease of the central nervous system that serves as an experimental model for multiple sclerosis. Autoimmune diseases such as EAE could be prevented or treated by administering attenuated, but potentially virulent autoimmune T cells specific for the disease-related self-antigens, a procedure called T-cell vaccination (TCV). It was discovered some years ago that T-cell vaccination can be used to treat autoimmunity, graft rejection, or allergies. The effect of TCV was hypothesized to be partially mediated by the in vivo activation of anti-ergotypic T cells (Lohse et al 1989).
Anti-ergotypic regulation is thought to be essential to successful T-cell vaccination (Zhang et al 1993; Van der Aa et al 2003), an approach currently being used to treat a variety of autoimmune diseases (Zhang et al 1993) and to prevent graft rejection (Shapira et al 1993) and allergy (Zhang et al 1993). Thus, agents that can activate anti-ergotypic regulation could have a wide use for all conditions where it would be desirable to modulate immune inflammation.
A preferable method for treating autoimmune diseases includes modulating the immune system of a patient to assist the patient's natural defense mechanisms. Traditional reagents and methods used to attempt to regulate an immune response in a patient also result in unwanted side effects and have limited effectiveness. For example, immunosuppressive reagents (e.g. cyclosporin A, azathioprine, and prednisone) used to treat patients with autoimmune diseases also suppress the patient's entire immune response, thereby increasing the risk of infection. In addition, immunopharmacological reagents used to treat cancer (e.g. interleukins) are short-lived in the circulation of a patient and are ineffective except in large doses. Due to the medical importance of immune regulation and the inadequacies of existing immunopharmacological reagents, reagents and methods to regulate specific parts of the immune system have been the subject of study for many years.
Stimulation or suppression of the immune response in a patient can be an effective treatment for a wide variety of medical disorders. T lymphocytes (T cells) are one of a variety of distinct cell types involved in an immune response. The activity of T cells is regulated by an antigen, presented to a T cell in the context of a major histocompatibility complex (MHC) molecule. The T cell receptor (TCR) then binds to the MHC-antigen complex. Once antigen is complexed to MHC, the MHC-antigen complex is bound by a specific TCR on a T cell, thereby altering the activity of that T cell.
WO 01/57056 of Karin discloses a method of treating rheumatoid arthritis of an individual. The method comprises the step of expressing within the individual at least an immunologically recognizable portion of a cytokine from an exogenous polynucleotide encoding the at least a portion of the cytokine, wherein a level of expression of the at least a portion of the cytokine is sufficient to induce the formation of anti-cytokine immunoglobulins which serve for neutralizing or ameliorating the activity of a respective and/or cross reactive endogenous cytokine, to thereby treat rheumatoid arthritis. U.S. Pat. No. 6,316,420 to Karin and coworkers further discloses DNA cytokine vaccines and use of same for protective immunity against multiple sclerosis.
WO 00/27870 of Naparstek and colleagues discloses a series of related peptides derived from heat shock proteins Hsp65 and Hsp60, their sequences, antibodies, and use as vaccines for conferring immunity against autoimmune and/or inflammatory disorders such as arthritis. These peptides are intended by the inventors to represent the shortest sequence or epitope that is involved in protection of susceptible rat strains against adjuvant induced arthritis. These sequences further disclose what the inventors identify as the common “protective motif”.
WO 03/096967 of the inventors and others discloses DNA vaccines for treating a T cell mediated inflammatory autoimmune where the DNA vaccine includes a recombinant construct comprising a nucleic acid sequence encoding a mammalian heat shock protein.
There are a number of disclosures using peptides derived from specific T Cell Receptors as therapeutics for immune-related disease. For example, U.S. Pat. No. 5,614,192 discloses peptides capable of reducing the severity of a T cell mediated disease having an amino acid sequence comprising at least part of the second complementarity determining region of a T cell receptor characteristic of such T cell mediated disease.
WO 94/19470 discloses prophylactic and therapeutic compositions for the treatment of autoimmune diseases which comprises a prophylactically or therapeutically effective amount of a soluble T-cell receptor α-chain produced by suppressor T-cells. Specifically, the '470 application discloses a composition comprising a soluble fragment of the variable region of a TCR α-chain obtained from KLH-specific suppressor T cells. More specifically, the use of a chimeric protein consisting of a variable region fragment of a mouse TCR α chain, denoted Vα14Jα281, fused to the constant region of mouse IgG, is disclosed.
WO 97/43411 discloses polypeptides that contain substantially part or the whole of the constant region of a T-cell receptor α-chain, having immunosuppressive effects, but do not substantially cause any production of antibodies against themselves even when administered. This application discloses DNAs coding for the polypeptides as well as pharmaceutical compositions containing these polypeptides as the active ingredient.
JP11302299 discloses polypeptides having immunosuppressive activity that substantially contain part or the whole of the constant region of T-cell receptor β-chain but do not substantially contain the other regions of the above β-chain.
A nine amino acid peptide derived from the transmembrane domain of the TCRα chain, denoted core peptide (CP), inhibits T-cell antigen specific activation in vitro and in vivo (Manolios et al., 1997) by co-localizing with the TCR molecules, thereby inhibiting the proper assembly of the TCR-CD3 complex.
U.S. Patent Application Publication No. 2005/0260770 to some of the inventors of the present invention discloses an antigen array system and diagnostic uses thereof. The application provides a method of diagnosing an immune disease or a predisposition thereto in a subject, comprising determining a capacity of immunoglobulins of the subject to specifically bind each antigen probe of an antigen probe set. The antigen probe set comprises a plurality of antigen probes selected from the group consisting of at least a portion of a cell/tissue structure molecule, at least a portion of a heat shock protein, at least a portion of an immune system molecule, at least a portion of a homopolymeric polypeptide, at least a portion of a hormone, at least a portion of a metabolic enzyme, at least a portion of a microbial antigen, at least a portion of a molluscan antigen, at least a portion of a nucleic acid, at least a portion of a plant antigen, at least a portion of a plasma molecule, and at least a portion of a tissue antigen, wherein the binding capacity of the immunoglobulin of the subject is indicative of the immune disease or the predisposition thereto. Among the numerous antigen probes disclosed by the '770 publication as potential diagnostic markers are peptides derived from a T cell receptor, preferably from the constant domain of rat T cell receptor beta chains.
Nowhere in the background art is it disclosed or suggested that specific peptides having therapeutic properties suitable for the treatment of autoimmune inflammatory disease may be derived from the constant domain of a T Cell Receptor polypeptide.
Recently, the inventors and coworkers (Mimran et al 2004) discovered that one of the target ergotopes on activated T cells is the CD25 molecule. In that publication, it was demonstrated that DNA vaccination with the ergotope CD25 protects rats from adjuvant arthritis and increases the anti-ergotypic response in rats where adjuvant arthritis was induced. This increased anti-ergotypic T cell response was defined by the heightened proliferative response to activated A6 T cell clones compared to the response observed in rats not vaccinated with the CD25-DNA vaccine. The increased anti-ergotopic T cell response was characterized by a reduction in the secretion of IFNγ and an increase in the secretion if IL-10, or in other words, a cytokine shift from a Th1-like to a Th2-like phenotype.
There exists a long-felt need for effective means of curing or ameliorating T cell mediated inflammatory or autoimmune diseases and ameliorating T cell mediated pathologies. Usually, only the symptoms can be treated, while the disease continues to progress, often resulting in severe debilitation or death. Such a treatment should ideally control the inappropriate T cell response, rather than merely reducing the symptoms.